The present study uses density functional theory to carefully consider the effects of the environment on the enhancement in (natural and damaged) DNA nucleobase acidities because of multiple hydrogen-bonding interactions. Although interactions with one small molecule can increase the acidity of the nucleobases by up to 60 kJ mol(-1) in the gas phase, the maximum increase in enzymatic-like environments is expected to be approximately 40 kJ mol(-1), which reduces to approximately 30 kJ mol(-1) in water. Furthermore, the calculated (simultaneous) effects of two, three, or four molecules are increasingly less than the sum of the individual (additive) effects with an increase in the number and acidity of the small molecules bound or the dielectric constant of the solvent. Regardless of these trends, our calculations reveal that additional hydrogen-bonding interactions will have a significant effect on nucleobase acidity in a variety of environments, where the exact magnitude of the effect depends on the properties of the small molecule bound, the nucleobase binding site, and the solvent. The maximum increase in nucleobase acidity because of interactions with up to four small molecules is approximately 80 kJ mol(-1) in enzymatic-like environments (or 65 kJ mol(-1) in water). These results suggest that hydrogen-bonding interactions likely play an important role in many biological processes by changing the physical and chemical properties of the nucleobases.